Methods of Non-a-Amino Acid Synthesis, 2nd Edition

75

4

Enolate Anion and

Related Reactions

An important general strategy for the preparation of amino acids involves generating

a carbanion from an acid derivative and subsequent reaction with another suitably

functionalized derivative. This reaction may be the conjugate addition discussed in

Chapter 3, Section 3.2.2, but alkylation or acyl addition reactions may also be used.

When appropriate functionality is present, these reactions constitute a useful route

to non-α-amino acids.

4.1 ACID, ESTER, AND MALONATE ENOLATE ANION REACTIONS

The reaction of an ester bearing an α-hydrogen atom with a nonnucleophilic base

such as lithium diisopropylamide (LDA) generates the corresponding enolate anion.

1

Modern techniques allow generation of both mono- and dianions of carboxylic acids.

Such enolate anions undergo C-alkylation and C-condensation reactions.

An example of an ester enolate alkylation reaction rst treated methyl 2-methyl-

propanoate with lithium diisopropylamide to generate the enolate anion, and then

with 4-bromobutanenitrile to give 1.

2

Catalytic hydrogenation of the cyano group

gave methyl 6-amino-2,2-dimethylhexanoate (2). In this case, the nitrile was the

amine surrogate and the ester was the acid precursor.

CO

2

Me

N

NH

2

CO

2

Me

CO

2

Me

Br

1. LDA, THF

–78°C

2. –70°C 0°C

H

2

, Ni (R)

EtOH, 100°C

90 atm, 1 h

12

69%

37%

C

N

C

The enolate alkylation reaction that generated 1 used cyano as a nitrogen sur-

rogate (see Chapter 1, Section 1.1.3). Other nitrogen surrogates may also be used

in enolate alkylation reactions. An example is the reaction of the sodium enolate of

diethyl 2-methyl malonate with phthalimide derivative 3. This displacement reaction

was followed by removal of the phthalimidoyl group, hydrolysis of the ester moieties,

and decarboxylation to give 2-methyl-6-aminohexanoic acid (4).

3

Phthalimide 1 was

prepared by reaction of 1,4-dibromobutane with potassium phthalimide.

3

The length

1

See Smith, M.B. Organic Synthesis, 3rd ed. Wavefunction, Inc./Elsevier, Irvine, CA/London, England,

2010, pp. 823–829.

2

(a) Cefelín, P.; Lochman, L.; Stehlícek, J. Coll. Czech. Chem. Commun. 1973, 38, 1339; (b) Cefelín, P.;

Lochman, L. Czech. 161,459 [Chem. Abstr. 1976, 85: P143778a].

3

Overberger, C.G.; Parker, G.M. J. Polym. Sci. A-1 1968, 6, 513. Also see Böhme, H.; Broese, R.; Eiden,

F. Chem. Ber. 1959, 92, 1258.

76

Methods of Non-α-Amino Acid Synthesis, Second Edition

of the carbon chain and the substituent pattern in the nal amino acid is determined

by the halo-phthalimide precursors.

N

Br

O

O

H

2

N

Me

CO

2

H

Me

CO

2

Et

CO

2

Et

2. HCl

3. IR 34 resin

34

1. NaH,

63%

One advantage of using a malonate derivative is the ability to incorporate either

one or two alkyl groups at the α-position via subsequent alkylation. Dibenzyl malo-

nate was methylated via reaction of its sodium enolate with iodomethane, and then

later condensed with α-bromo-ketone 5 to give 6.

4

Catalytic hydrogenation deprot-

ected the esters to give the diacid, and heating led to decarboxylation and formation

of 6-(N-Boc amino)-3,8-dimethyl-5-oxononanoic acid, 7. Malonate anions also react

with α-amidoalkyl-p-tolyl(phenyl)sulfones in the presence of a base to give β-amino

diacid derivatives.

5

Subsequent hydrolysis, with deprotection and decarboxylation,

gave the amino acid.

CO

2

Bn

CO

2

Bn

BocHN

O

Br

BocHN

O

CO

2

Bn

Me

BnO

2

C

BocHN

O

HO

2

C

Me

3.

1. NaH, HMPA, DMF

2. MeI

1. H

2

, Pd-C

MeOH

2. Py, 100°C

5

6

7

Ester enolate anions react with other electrophilic substrates, including imino

chlorides. Peruorinated β-amino acid derivatives were prepared by condensation of

an ester enolate anion with a triuoromethyl imino chloride to give enamino-esters

such as 8.

6

Subsequent reduction gave the amino-ester, 9. β-Triuoroalkyl β-amino

acids were also prepared via a base-catalyzed [1,3]-proton shift reaction.

7

OMe

F

3

C OMe

N

F

3

C Cl

PMP

NH

PMP

O

O

PMP = p-methoxyphenyl

1. 2 LDA, THF

–78°C

2. aq NH

4

Cl

8 92%

(60:40 imino:enamino)

3 ZnI

2

, DCM, rt, 1d

NaBH

4

90% (98:2 syn:anti)

F

3

C OMe

NH

PMP

O

9

4

Harbeson, S.L.; Rich, D.H. J. Med. Chem, 1989, 32, 1378.

5

Nejman, M.; Śliwińska, A.; Zwierzak, A. Tetrahedron 2005, 61, 8536.

6

Fustero, S.; Pina, B.; García de la Torre, M.; Navarro, A.; Ramírez de Arellano, C.; Simón, A. Org.

Lett. 1999, 1, 977.

7

Soloshonok, V.A.; Kukhar, V.P. Tetrahedron 1996, 52, 6953.